Vaccines are among the most effective interventions in modern medicine. Ever since Edward Jenner's first use of a vaccine against smallpox in 1796, the use of vaccines has become indispensable to the eradication of disease (Gary J. Nabel, 2013). Vaccines are used to elicit the specific immune responses against a particular target antigen. For example, vaccines against viral or bacterial components are used to prevent or limit infection caused by the respective pathogen (I. P. Nascimento et al, 2012). Vaccines against tumor specific antigens or a combination of such antigens are used in the treatment of cancer (Tagliamonte M et al, 2014), However, to an unprimed immune system, target antigens are typically poor at stimulating the specific immune responses on their own, especially in vaccines where the immunizing antigen is an isolated or synthesized peptide. To overcome this, commercial vaccine preparations typically contain not just the target antigen, but also an immunological adjuvant (Alberta Di Pasquale et al, 2015).
A vaccine adjuvant is more precisely a particulate, solid or soluble agent that increases the specific immune responses to an antigen. Vaccine adjuvants can enhance the immune responses to vaccine antigens in various ways. They are very useful for augmenting the immunogenicity and vaccine potency of weak antigens. They are used to enhance the speed, vigor, and persistence of the immune responses to strong antigens. The vaccine adjuvants are useful for potentiating the immune responses in immunologically immature, immune-suppressed or senescent individuals, acting as an immunological booster. Also, the vaccine adjuvant can effectively decrease the dose of antigen and/or the frequency of injection necessary to provide protection (Robert L et al, 2010; Marciani D J, 2003).
Antigens have been combined with aluminum-containing adjuvant since 1926, when Glenny and colleagues originally precipitated diphtheria toxoids with aluminum salt and observed an unproved immune response over a soluble antigen inoculation (A. P. C. Glenny et al, 1926). The most widely used adjuvant in medicine is aluminum that is used in both human and veterinary vaccines under the form of aluminum salts. An important formulation and stability concern for vaccines with aluminum salts is their reduced efficacy following freeze-thaw stress. Exposure to freeze-thaw stress results in agglomeration of the vaccines containing aluminum salts and vaccine potency loss. In addition, whereas aluminum salts stimulate the strong immune responses to the specific antigen (Baylor N W et al, 2002), its toxic effects (neurological toxicity, autoimmunity) are well but only partially known (Kumar V et al, 2009; Shaw C A I et al, 2013). The safety of aluminum salts as a vaccine adjuvant is still being concerned (Tomljenovic L. et al, 2011).
Oil-in-water emulsions have gained interest as adjuvants on account of substantial increases in the quality of the elicited immune responses compared with traditional aluminum salts based adjuvants (G. Leroux-Roels, 2010; F. R. Vogel et al, 2009). However, most emulsions cannot be readily frozen or lyophilized, on account of the risk of phase separation, and may have a deleterious effect on protein antigen stability when stored long term as a liquid co-formulation. Typically, the protein antigen and the emulsion must be mixed together just before administration to obtain the optimal efficacy (G. L. B. Gary Ott et al, 1995).
The Toll-like receptor (TLR) adjuvant category covers an extremely broad spectrum of pathogen-derived compounds including nucleic acids, proteins, lipopeptides and glycolipids, and synthetic analogues thereof (Petrovsky N et al, 2004). Each of these types of compounds is likely to have very different toxicities. All TLR agonists activate the inflammatory transcription factor, NFkB, through the TLR adaptor proteins, MYD88 and TRIF (Verstak B et al, 2007). A consequence of NFkB activation is production of pyrogens and inflammatory cytokines. NFkB activation may be involved in the induction of chronic inflammation and autoimmune reactions (Collins S E et al, 2014; Akbar Mohammad Hosseini et al, 2015).
Many vaccines are thermally labile, which can challenge distribution and storage of vaccines in countries where cold-chain management is difficult (Brandau D T et al, 2003). The development of thermostable products can help with the distribution of vaccines in these areas, and can also help reduce waste of product that has inadvertently been stored at temperatures that exceed or fall below specified storage temperatures. At this point, lyophilization of vaccines is of great interest. Lyophilization of vaccines is advantageous for the distribution and storage of thermally labile products, particularly in regions where cold-chain management is difficult. In addition, lyophilized formats have potential to provide for longer product shelf lives. Vaccines containing aluminum salt or oil-in water emulsion adjuvants generally could not be lyophilized. To date, current lyophilized vaccines do not contain an adjuvant. Instead, adjuvanted vaccines may be presented as a two vial system, that require bedside-mixing prior to immunization.
World Health Organization (WHO) guidelines and manufacturer product inserts recommend that all vaccines except oral polio vaccine be kept at 2-8° C. during in-country distribution. This presents a significant financial and technological barrier to worldwide implementation of such vaccines. Additionally, cold-chain maintenance cannot be ensured during natural disasters when power supplies may be compromised. Development of adjuvanted vaccines that de not require cold-chain maintenance would significantly reduce the cost and technological hurdles of implementation of new vaccines worldwide, especially in low resource settings.
There is a need for developing new adjuvants which are safer and convenient to use. There is also a need for thermostable adjuvanted vaccines that are chemically stable at sustained temperatures and that retain the ability to elicit the immune responses against the vaccine antigens. As disclosed herein, the present invention meets these above-mentioned needs.